Synthesis of deoxygenated α(1 → 5)-linked arabinofuranose disaccharides as substrates and inhibitors of arabinosyltransferases of Mycobacterium tuberculosis

被引：15
|
作者：
Pathak, Ashish K. [1 ]
Pathak, Vibha [1 ]
Suling, William J. [1 ]
Riordan, James R. [1 ]
Gurcha, Sudagar S. [2 ]
Besra, Gurdyal S. [2 ]
Reynolds, Robert C. [1 ]
机构：
[1] So Res Inst, Drug Discovery Div, Birmingham, AL 35255 USA
[2] Univ Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 02期
基金：
英国医学研究理事会;
关键词：
Arabinosyltransferases; Mycobacterium tuberculosis; Deoxyarabinofuranose; 2-Fluoroarabinofuranose; Disaccharides; Inhibitors; DRUG-RESISTANT TUBERCULOSIS; HIV-INFECTED PATIENTS; STEREOSELECTIVE-SYNTHESIS; MULTIDRUG-RESISTANT; TRANSFERASE-ACTIVITY; DERIVATIVES; ANALOGS; GLYCOSYLATION; BIOSYNTHESIS; EPIDEMIOLOGY;
D O I：
10.1016/j.bmc.2008.11.027
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Arabinosyltransferases (AraTs) play a critical role in mycobacterial cell wall biosynthesis and are potential drug targets for the treatment of tuberculosis, especially multi-drug resistant forms of M. tuberculosis (MTB). Herein, we report the synthesis and acceptor/inhibitory activity of Araf alpha(1 -> 5) Araf disaccharides possessing deoxygenation at the reducing sugar of the disaccharide. Deoxygenation at either the C-2 or C-3 position of Araf was achieved via a free radical procedure using xanthate derivatives of the hydroxyl group. The alpha(1 -> 5)-linked disaccharides were produced by coupling n-octyl alpha-Araf 2-/3-deoxy, 2-fluoro glycosyl acceptors with an Araf thioglycosyl donor. The target disaccharides were tested in a cell free mycobacterial AraTs assay as well as an in vitro assay against MTB H37Ra and M. avium complex strains. (C) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码：872 / 881
页数：10
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